JPH07508728A - 1-Allyl(4-o-alkoxyphenyl 1-piperazinyl)-2, -3 or -4 alkanols and methods of their preparation and use thereof in the preparation of drugs. - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] 1-Allyl(4-0-alkoxyphenyl l-piperazinyl)-2, -3 or -4flucanol, its preparation method and its use in the preparation of drugs The present invention provides l-allyl-2-1-3- or -4-(4-o-alkoxyphenyl Piperazin-1-yl) alcatul, its preparation method and urethral hypertonia or benign For the preparation of drugs specifically intended for the treatment of urinary disorders related specifically to prostatic hypertrophy. and how to use it.

The compounds of formula I below have extremely valuable pharmacological properties and are well suited for therapeutic use. It has been discovered that the resulting compounds have low toxicity, and this forms the basis of the present invention. Especially this The novel pharmacological properties of the compound make it particularly relevant to advanced urethral tone or benign prostatic hyperplasia. It becomes possible to consider the use of such compounds in the treatment of related urinary disorders.

The above compound has the following general formula.

In the formula: -R, , R, and R1 are the same or different, and each represents a hydrogen atom or a hydroxyl group. and methoxy group; R4 is a hydrogen atom, and! to 5 carbon atoms an alkyl group selected from; -〇 represents an integer from 1 to 3: It is expressed as

Alkyl radicals are understood to represent linear or branched hydrocarbon chains. Carbon number 1 The alkyl group of 5 to 5 is, for example, methyl, ethyl, propyl, isopropyl, but tyl, isobutyl, tert-butyl, or pentyl group, preferably ethyl It is a thyl or isopropyl group.

Compounds 2) are particularly suitable for pharmaceutically acceptable inorganic compounds such as, for example, hydrochloric acid or sulfuric acid. acids, such as citric acid, tartaric acid, malic acid, maleic acid, fumaric acid or May form addition salts with pharmaceutically acceptable organic acids such as methanesulfonic acid .

Moreover, compounds of formula I with asymmetric carbon atoms may be formed into specific enantiomers or racemized may form compounds.

Viewed as products, none of the compounds of formula I described above are new.

Therefore, it is represented by the above formula I, where R2 represents a hydrogen atom and R1 and R2 simultaneously represent a hydroxyl group and occupy the 3rd and 4th positions of the phenyl ring, respectively (the 1st position is substituted with alkanol), R4 has 1 to 1 carbon atoms. Compounds representing an alkyl group of 5 and n corresponding to 1 are particularly suitable for use in France (FR ) Patent No. 1483 416 Specification and French Patent (FRM) No. 5977 It is well known from the specification. Moreover, it conforms to formula I, in which R1 represents a hydrogen atom. However, one of R1 and R2 represents a hydrogen atom, and the other represents a hydrogen atom or a methoxy group. where R4 represents a lower alkoxy group and n is an allylbutanol derivative equal to 3. The conductor is known from French Patent (FR) No. 2 073 326. Ru. Furthermore, in accordance with formula I, R, , R and R2 simultaneously represent a hydrogen atom. , R4 represents a methyl radical, allylbutanol is described in European Patent No. 0395312 No. 0479546 and European Patent No. 0395313 It is well known.

According to a first characteristic, the invention therefore provides novel products of the formula I: , where R, , Ra, R, , R, and n are defined as above, but if n and R2 represents a hydrogen atom, R1 and R2 represent the tertiary group of the phenyl ring. There are no hydroxyl groups at the same time at the and fourth positions, and R1, R2 and R1 are at the same time. When representing a hydrogen atom, R1 is not a methyl radical and n corresponds to 3 The aim is for at least one of R1 and R1 to constitute a compound representing a hydroxyl group. target

French Patent (FR) No. 1 483 416 and French Patent (FRM) The compounds disclosed in No. 5977 are useful for the treatment of hypertonia and peripheral vascular disease. , therapeutically active substances in bronchospasm and indications for antihistamines and muscle relaxants It is necessary to pay attention to the fact that it is written as

On the other hand, French Patent (PR) No. 2 073 326, European Patent No. 039 5312, European Patent No. 0395313 and European Patent No. 0479546 The compounds described in this book are synthetic intermediates used in the preparation of allyl ketone derivatives. Only the following will be shown.

Therefore, for use as a therapeutically active substance, the present invention is represented by formula I above: where R, , R, , R, , R, and n are defined as above, provided that n is 1. If they match, R3 and R2 are the same in the 3rd and 4th positions of the phenyl ring, respectively. Sometimes it consists of compounds that do not represent hydroxyl groups.

For convenience of explanation, the above compound will be referred to in the following explanation [as compound j of formula (IA)] show.

Therefore, the present invention is useful in the field of urology, particularly in the treatment of urethral hypertonia or benign prostatic hyperplasia. Further relating to drugs particularly useful in the treatment of related urinary disorders, such drugs are at least - of the above formulas in conjunction with excipients, excipients or carriers that are acceptable for (IA) or one of its pharmaceutically acceptable salts as an active ingredient. nothing.

A pharmaceutically acceptable salt of formula (IA), such as a hydrochloride salt, is a salt of formula (TA) can be obtained by well-known methods of contacting compounds with inorganic or organic acids. . For example, hydrochloride is a solution of hydrochloric acid titrated in alcohol to a compound of formula (TA). obtained by adding it to a solution of a substance.

The above addition salts may, of course, be added in an amount of 1 to 2 moles of chloride per mole of the compound of formula (IA). Contains acid.

The present invention is directed to the field of urology, particularly those related to urethral hypertonia or benign prostatic hyperplasia. further relates to a method for preparing a drug particularly useful for the treatment of urinary disorders, such method comprising: at least one of the above-mentioned compounds of formula (IA), or a pharmaceutically acceptable salt thereof; as an active ingredient in a pharmaceutically acceptable excipient, pill or base; Consisting of

The compound of formula (1) or (IA) is prepared by converting the compound of formula (II) into ethanol. Reduction using a reducing agent such as sodium borohydride in a solvent such as More can be obtained.

Reactions of the above type are fully described in the literature to which the person skilled in the art may refer.

The compound of formula (II) is a compound of formula (III): where: R+, R2 and R2 are as defined above. as defined; X represents a halogen atom, preferably bromine or chlorine; The halogenated ketone represented by the formula (IV): where: -R4 is defined as above. is similar to: Reacting with 0-alcoquinophenylpiperazine represented by It is obtained by

Such reactions are preferably carried out using triethyl chloride in a solvent such as tetrahydrofuran. It is carried out in the presence of a hydrogen acid acceptor such as ruamine.

Formula (I).

The enantiomer of the compound represented by formula (V): where R3, Rt and R2 are As defined above: X represents a halogen atom, preferably bromine or chlorine; A chiral halogenated alcohol represented by the formula (IV): where - R4 is as defined above: 0-alkoxyphenylpiperazide represented by It can be obtained by reacting with

The above reaction is preferably carried out using a tertiary amine, especially a water-based amine such as triethylamine. carried out in a solvent such as THF, benzene or toluene in the presence of an oxygen acceptor. Alternatively, the reaction may be carried out under non-racemizing conditions without the use of a solvent.

Generally, compounds of formula (V) are of the formula (Vl): where -R1, R2 and R1 are As defined above, X represents a halogen atom, preferably bromine or chlorine. A prochiral ketone represented by: can be reduced, for example, according to the following formula and references: It can be obtained by

The reduction with BH, THF above uses S or R according to the desired enantiomer. This is done using Corey's chirality aid: S-(-)-2-methyl-CBS-oxazaporolidine R-(+)-2-methyl -CBS-Oxazaborolidine (Reference Lancaster 9219 and 9230) EJ, Corey, R, K, Bakshi, S, Shibata, Transactions of the Japanese Society of Organic Chemistry, Vol. 53, pages 2861-2863 (published in 1988).

Generally, compounds of formula (III) can be prepared, for example, according to the formula and references below. 5 by halogenating the corresponding substituted acetophenone. M, L, Malikike, Journal of the Chemical Society of India, Volume 14B, Pages 513-515. (published in 1976).

Similarly, the compound of formula (TV) is a 2-alcokyne according to the formula and references below. Obtained from aniline.

Buysouth, Beater T., and Clark, Robert W., 1969 1 South African Patent No. 6804.082 dated July 5, 1967 For dates see UK patent application specification.

The above 2-alkoxyanilines can be prepared using experimental methods well known to those skilled in the art. , by alkylating the 2-acetamidophenol and then deprotecting it. can get.

The invention will be explained below by way of non-limiting examples.

Example 1 l-(2,5-dimedquinphenyl)-2-(4-o-isopropoxyphenyl Piperazin-1-yl) ethanol synthesis coat name = BI450 R, = isopropyl n=1 The product is in the form of its hydrochloride.

The following experimental record first began with 2-bromo-3,4-dimethoxyacetophenone ( A) and then 1-(2-isopropoxyphenyl)piperazine (B) used to prepare.

C+oH++BrOx=259. Equipped with a bubbler filled with 11 sulfuric acid. In 21 flasks with three necks containing a condenser -123.94g (0,555mol) of cuprous bromide is dried in 600ml Suspended in ethyl acetate (greenish, heterogeneous medium) with magnetic stirring.

Then 50 g (0,277 m.) dissolved in dry chloroform.

A 600 ml solution of 3,4-dimethoxyacetophenone from l) is added.

The reaction medium is heated to the reflux point. Release of hydrobromic acid is observed. 5 hours 1& Next, the salt is separately filtered and washed with pentane.

The organic phases are combined and washed with a saturated aqueous solution of sodium chloride (p’H4) . These are dried with sodium sulfate.

The organic solvent is evaporated in vacuo. The resulting crystals are washed with pentane and hexa It is recrystallized from a mixture of carbon/ethanol (+/1).

This gives 45.53 g of purple crystals that melt at 80-82°C ( Yield: 63.3%). Purity is 97% (GC).

C1 + H1s N O□ = 193.25 Equipped with a bubbler filled with sulfuric acid Three necks with condenser, pneumatic stirrer, thermometer and drip funnel In 41 flasks with -73.13 g (3.14 gram atoms) of sodium is added to 2°31 of anhydrous ethanol. Partially dissolved in water.

470 g (3,10 mol) of 2-acetamide in 1200 ml of ethanol Do-phenol solution is added.

The homogeneous medium is refluxed for 20 minutes and cooled to 50°C. 615g (5mol) of 2-bromo-propane was added dropwise over a period of 55 minutes and the reaction medium was allowed to cool for 2 hours. It is refluxed for a period of time.

The salts formed are separately filtered and washed with ethanol. alcohol phase is true Evaporated in the sky.

The residue was taken up with ethyl ether and washed with IN sodium hydroxide and water. , dried with sodium sulfate.

A slightly crystallized brown oil is obtained. This oil is distilled under vacuum.

B, P, (boiling point) / o, os-b- = 100 to 118°, 599 g of yellow oil are obtained which crystallizes (yield 7896). that yellow color The crystals melted below 50°C. This crystal has one spot on the TLC of 5iCh. (CH, C12/MeOH is 9/l) and has a purity of 99.7% (GC). do.

82. Synthesis of 2-isoproboxoaniline C++*H1zNO=151. 21 4I flask with 3 necks to house condenser, thermometer and air stirrer within the - 468.30g (2,433mol) of 1-acetamidoisopropoxybenzene 1875 ml of 18% hydrochloric acid.

The reaction mixture is refluxed for 1 hour. Solubilization of organic compounds is observed.

The solution is cooled in a water bath and made basic with 30% aqueous ammonia (p H9).

The reaction medium is extracted with methylene chloride; Washed several times with water until 6. After drying with sodium sulfate and filtration, The methylene chloride phase is evaporated to dryness in vacuo.

A brown oil of 363, log is obtained and distilled in vacuo: B, P, /. 2 ．． bo, = 68-70°C 357,0g of yellow oil is recovered (collected rate 98%). This product gives one spot on TLC at 5ift. (CHt CI-/Me OH is 9/1). (CGC purity is 100%) .

Its infrared spectrum is consistent with the intended structure.

Cl5Ht + ClNa O = 256.77 8 + 404 condenser, thermometer, in a three-necked 41 flask with an air stirrer. -356,33g (2,356mol) of 2-isopropoquinaniline is 16 Dissolved in 50 ml of dry butanol.

-504,62g (2,827mol) of 2,2'-dichlorodiethylamide ion hydrochloride pink uneven medium 249.72 g (2,356 mol) of anhydrous sodium carbonate was added in one portion. It will be done.

The reaction medium is then refluxed for 3 days.

The course of the reaction is monitored by gas chromatography.

Insoluble material was separately filtered through a glass frit and added to 3 x 500 ml of butanol. Washed with water. The butanol phase is evaporated in vacuo. The red crystals obtained are , washed with ethyl ether and acetone, and vacuum dried at 50°C with phosphorous pentoxide. , thus 100% purity in GC and one drop in TLC of 5 iOz. Pin that produces a pot (CH2C12/MeOH/NH, OH is 80/20/2) 448g of dark colored crystals (yield 74%)? ! ) can be done. Pure as determined by silver titration The degree is 9978% and the infrared spectrum is consistent with the intended structure. the above The hydrochloride of sublimes at 190°C.

B4. Synthesis of I-(2-isopropoquinphenyl)piperazine C1: H2o N 20 = 220.32 in +01 reactor with only air stirrer.

445.80g (1,736mol) of 1-(2-isopropoquinphenyl) piperazine hydrochloride is dissolved.

After cooling in the water bath, a small amount of 440 ml of 30% sodium hydroxide is added. . The reaction mixture is stirred at room temperature overnight and extracted several times with ethyl alcohol.

The ether phase was washed with a saturated aqueous solution of sodium chloride (until the pH of the wash reached 6). ), dried over sodium sulfate, filtered and evaporated in vacuo.

363.7 g (95% yield) of brown oil was recovered and distilled in vacuo. B, P, /. . +-,, = 105-110°C 352g (yield 92%) colorless oil: no”=1.5440 was obtained, and this oil was 1 The purity is 100.12% by perchlorine method.

The infrared spectrum is consistent with the mapped structure.

1al-(2,5-dimethoxyphenyl)2-(4-o-isopropoquinphenylphenyl) L-piperazin-1-yl)ethanone C2,H,. N201 = 398.49 sulfur 11 flasks with 3 necks with condenser with acid-filled bubbler Within SC.

-25g (0,0965mo+) of 2-bromo-3,4-dimethoxyacetophyl Enon and -13,45m1 (0,0965mo+) of triethylamine is 275m1 Dissolved in THF (tetrahydrofuran) with magnetic stirring.

19.32 g (0,08 77 mol) of 1-(0-isopropoxy7ale)piperazine solution was added dropwise. be introduced.

Precipitation is observed. Stirring is continued for 12 hours.

After filtration over a glass frit, the THF is evaporated in vacuo.

The residue is taken up with ethyl ether. Yellow oil after conventional acid/base treatment :28.2g, ie, a yield of 173.3% was recovered.

lb 1-(2,5-dimethoxyphenyl)-2-(4-o-isopropoxyphenyl (phenyl)-piperazin-1-yl)ethanone hydrochloride C22H3°N, O,,H CI = 434.95 The 28.2g of oil obtained above is Dissolved in tanol. 27 ml of 202N hydrogen chloride solution is introduced into ethanol be done.

The resulting solution is stirred for 1 hour. The ethanol is removed in vacuo and the residue is absorbed and crystallized with ethyl acetate. The obtained crystals are separated using a glass frit. Separately filter and wash with ethyl ether.

The above crystals are recrystallized from isopropyl alcohol.

This yielded 19.66 g of white crystals that melt at 202-204°C. (Yield JL: 82.9%).

TBAH assay results・Purity 964% 1cl-(2,5-dimethoxyphenyl )-2-(4-o-isopropoxyphenyl-piperazin-1-yl)ethanol Le C HstN * 04 = 400.5 17.49g obtained in 1b above ( 0,0402 mol) of hydrochloride was dissolved in 20 (1 ml of MeOH and heated at -6 °C treated with 4.79 g (0,127 mo+) of sodium borohydride at a temperature of be done. The mixture is stirred for 12 hours.

The reaction medium was poured onto ice, acidified with acetic acid, neutralized with sodium bicarbonate, and evaporated with ethyl alcohol. The organic phase is washed with water and dried with sodium sulfate: and condense in a vacuum.

This resulted in 15.9 g of oil with a purity (GC) of 97.7% (yield 98 ゜8%) can be obtained.

1d 1-(2,5-dimethoxyphenyl)-2-(4-o-isopropoquinf phenyl-piperazin-1-yl) ethanol hydrochloride C23H2, NtOa, HC I = 436.98 14.5g (0,0362mo+) of the above IC compound 2.02N hydrogen chloride solution in ethanol dissolved in 400ml ethanol It is processed in 27ml.

After 1 hour of contact, the solution was evaporated in vacuo and the residue was absorbed with ethyl acetate. was collected, crystallized and filtered on a glass frit.

The white crystals were recrystallized from a mixture of hebutane and isopropanol (55/45). be done.

This melts at 178-180°C and is evaluated by potentiometric assay using silver nitrate. 11.92 g of white crystals (75% yield) with a purity of 103.5% were obtained. It will be done.

Example 2 1-phenyl-4-(4-o-ethoxyphenylpiperazin-1-yl)butane Synthesis code name of -1-yl monohydrochloride = BI567 n=1 The product is in the form of the monohydrochloride salt.

2a l-phenyl-4-(4-o-ethoxyphenylpiperazin-1-yl) Butanone hydrochloride C22HtlN20t, HCI = 388.93 Ni in round bottom flask -12.78g (0.07mol) of 4-chlorobutyrophenone, -14,43 g (0,07 mol) of 1-(0-xtoxyphenyl)-1-pipe Radin and -11 ml of triethylamine is Heat with stirring at a temperature of 80-90°C for 17 hours.

The reaction mixture is taken up with 100 ml of ethyl ether. Discard the crystals that form. to acidify the ether phase.

16.9 which melts between +30 and 132°C and has a purity of 102.5% (argentometric titration) 6 g of white crystals (69% yield) are recovered.

2b l-phenyl-4-(4-o-ethoxyphenylpiperazin-1-yl) Butan-1-yl monohydrochloride C22H,,N,02. HCI = 390.9 5 16.96g (0,0434mol) of butanone from 2a above is 250m 5.74 g (0,+52 mol) of borohydride dissolved in 1 part of methanol Sodium is partially added. The reaction mixture was allowed to stand overnight without stirring. Ru.

After evaporation of methanol in vacuo and absorption with water, extraction is carried out with ethyl acetate. It will be done. The organic phase is washed with a saturated aqueous solution of sodium chloride until the washings are neutral. Ru. The organic phase is dried with sulfate.

The resulting oil was dissolved in 350 ml of anhydrous ethyl ether and diluted in ethanol. of 2.18N hydrogen chloride solution.

The precipitate that forms is separately filtered, washed with ethyl ether and dried under vacuum. Ru.

The crystals were recrystallized from a mixture of ethyl acetate and methanol (100/35). Ru.

This yields 1, which melts at 186-187"C and has a purity of 98% (argentometric titration). 1.4 g of white crystals are obtained, ie 71% yield.

Example 3 l-(3,4-dimethoxyphenyl)-2-(4-o-ethoxyphenylpipera Synthesis code name of (dinyl) ethanol monohydrochloride = BI614 Formula I The product is in the form of the monohydrochloride salt.

3al-(3,4-dimethoxyphenyl)2-(4-o-ethoxyphenylpipe Radinyl) ethanone has a condenser with a bubbler filled with hydrochloride sulfuric acid In a 500 m1 flask with three necks, 25 g of knee (0,09 65 mol) of 2-bromo-3',4'-nomethoxyacetophenone, -13,45 m1 (0,0965 mol) of triethylamine is 100 m1 Dissolved in THF (tetrahydrofuran) with magnetic stirring.

At room temperature, 19.9 g (0,0965 mo+) of 1-(0-ethoxyphenyl) 100 ml of a solution of piperazine in THF are introduced dropwise. slight Fever is observed.

The solution is stirred for 92 hours. Occurrence of precipitation is observed. Such precipitates are separated by filtration. and the THF was evaporated in vacuo.

The remaining oil is absorbed with ethyl ether and crushed. The yellow crystals obtained are Recrystallized from a mixture of san and ethanol (5/1).

This results in crystals that melt at 96-98°C and have a purity of 97.3% (GC). (yield 52%).

The above crystals were dissolved in ethyl acetate and in an anhydrous ethanol solution of hydrogen chloride. It is processed. The white hydrochloride precipitate is separately filtered through a glass frit and Washed with chill ether and dried with phosphorous pentoxide in a vacuum kiln.

Recrystallization yields a product that melts at 210-215°C; S10. produces only one spot on TLC (CH,C1,/MeOH95 15).

phenylpiperazinyl) ethanol 19.9g (0,0473mol) of hydrochloride obtained in 3a above is 10100 8.95 g (0,23 7 ml of sodium borohydride. The reaction medium was stirred for 12 hours. be done.

Methanol is removed in a rotary set evaporator to obtain white crystals, and the above crystals is absorbed by 300 ml of water and 300 ml of ethyl acetate.

The organic phase is washed with a saturated aqueous solution of sodium chloride until the pH of the wash reaches 5.

After drying with sodium sulfate, the solvent is evaporated in vacuo.

This yielded 17.68 g of beige crystals, or a yield of 96.77%. It will be done. This product melts between 99 and 101'C.

3cl-(3,4-dimethoxyphenyl)-2-(4-o-ethoxyphenylpi perazinil) ethanol monohydrochloride 17.14g (0,044mol) 3 The compound obtained in step b was dissolved in 180 ml of anhydrous methanol and dissolved in ethanol. 22° with 5 ml of 1.93N hydrogen chloride solution.

The mixture is stirred for 30 minutes at room temperature.

The medium is evaporated to dryness in vacuum. The crystals obtained are ethyl ether washed with water, separately filtered with a glass frit and dried with phosphorous pentoxide in vacuo. It will be done.

This produces 18.92g of white crystals that melt at 197-198°C, i.e. Amount of 97.8% is obtained.

The above crystals are recrystallized from ethanol. The crystal is 198 to 200° It has a purity (argentometric titration) of 100.496.

Examples 4 to 24 Other compounds whose empirical formulas, molecular weights, melting points, and silver nitrate titers are shown in Table I are those of ordinary skill in the art. Experimental treatments similar to those described in Examples 1 to 3 above, as will be readily ascertained by those skilled in the art. prepared using.

Details of the synthesis of Examples 20 and 2I are described below.

delivery S-(+)-1-(2,4-dimethoxyphenyl)-2-(4-(0-ethoxy Synthesis of phenyl)piperazin-1-yl)ethanol monohydrochloride Code name = BI614 In formula 11 The product is in the form of its monohydrochloride.

-0,45g (1,52mmo+) of S-(-)-2-methyl-CBS-oxy Sazaborolidine and - Dissolve 9.5 ml of borane/THF complex in THF through the septum using a syringe. A 1 molar solution was prepared using two branched fittings, a condenser and a dripping , introduced into a three-necked flask equipped with a thermometer, syringe, and nitrogen sweep. and the whole is placed on a magnetic stirrer.

The reaction medium is stirred for 5 minutes.

- Then 3.25 g (15.24 mmol) of 2-bromo-2', 4'- A solution of dimethoxyacetophenone in 33 ml of anhydrous THF was added dropwise. added.

The temperature is maintained at 25°C in the water bath. The mixture is stirred for 8 hours.

A solution of 3.70 ml of HCI in MeOH (0.5 M) at 0 °C is added to the reaction medium. added.

The bright yellow medium takes on a white tinge: the formation of a white precipitate is observed.

The mixture is stirred for 1 hour.

Insoluble material was separately filtered through a glass frit and washed with 70 ml of n-butanol. Washed. The butanol phase was washed with a saturated aqueous solution of sodium chloride and then with sodium sulfate. dried in a lium.

The butanol is removed in vacuo and the residue is taken up with anhydrous THF.

The amount of brominated alcohol thus obtained can be determined by using CHCl3 as eluent. Verified by TLC on 5 iOz.

Enantiomeric excess is assessed by HPLC on a chiral column [D(4-(o-E) Toxyphenyl)piperazin-1-yl]ethanol monohydrochloride (BI778 ) - 2.5 g (9,57 mmol) of 5-1-(2 ,4-dimethoxyphenyl)-2-bromoethanol; - 0,96 g (9,57 mmol) of triethylamine are added to the condenser and the dripper. The whole is introduced into a three-necked flask with a funnel and a thermometer. Place on magnetic stirrer.

- then 1.97 g (9.57 mmol) of 1-(0-ethylene chloride) in anhydrous THF A 25 ml solution of piperazine (xyphenyl) is added.

The reaction mixture is refluxed for 48 hours.

The THF is removed in vacuo and the residue is taken up with 400 ml of Ac0Et. organic The phase is washed with water until the washings are neutral, dried over sodium sulfate, and filtered. and then evaporated to dryness in vacuo.

The brown oil is chloroform and CHCl! /acetone mixture (90/IO) It is purified by passing through a column of silica gel using as eluent.

This gives 2.68 g of orange oil, i.e. yield 7296 .

The above oil is dissolved in methanol, followed by a calculated amount of dry HCI gas. is added to produce the monohydrochloride.

The precipitated white crystals are separately filtered, washed with ethyl acetate and placed in a vacuum kiln. dried with phosphorous pentoxide in

The monohydrochloride salt melts between +78 and 179°C and reacts in one drop with 5 iOz TLC. Only a pot is produced (CH2C12/MeOH/NH40H95/4.510. 5).

Purity as determined by argentometric titration is 100%. Infrared spectrum and NMR spectrum The spectrum is consistent with the intended structure.

The optical rotation is (αgo” = +30 ± 1’ (0,5; MeOH).

Example 21 R-(-)-1-(2,4-dimethoxyphenyl)-2-(4-(0-ethoxy Synthesis of phenylpiperazin-1-yl ethanol monohydrochloride Code name = 81783 In formula 11 The product is in the form of the monohydrochloride salt.

The above compound is Corey's chirality aid R-(+)-2-methyl-CBS - an experimental treatment similar to that described in Example 20 using oxazaborolidine; More can be obtained. The empirical formula, molecular weight, melting point and silver nitrate titer are shown in Table I.

The toxicopharmacological properties of the products that form the subject of the invention are described below.

1. Acute toxicity to mice a) Policy The above product was administered orally to mice in only one dose. Number of deaths increased over 14 days recorded throughout. The results are ``50% lethal ffi (LD) per mg, kg-'. s. ).

b) Results The results obtained are recorded in Table II.

Teddie II Acute toxicity to mice ++, Determination of alpha-blocking activity in isolated rat vas deferens. a) Policy Norepinephrine stimulates postsynaptic α-adrenergic receptors. This causes contraction of the isolated vas deferens. This is the case without the above products and Is it necessary to double the concentration of norepinephrine to achieve the same effect? The purpose is to detect the concentration of the product present.

The logarithm of the above concentrations, with the sign changed, constitutes the value of pA2 of the product.

b) Results The results are shown in Table II+. This result indicates that the product is highly sensitive to α-adrenergic receptors. Acts as a competitive antagonist of norepinephrine and has valuable alpha-blocking activity I understand that it involves sex.

Table IfI Alpha-blocking effect of the product in isolated rat vas deferens I11 Determination of in vivo anti-adrenergic activity in rats a) Policy Norepinephrine (0.4 mg, kg”) was administered intravenously to awake rats. 100% ecology or death. Preliminary preparation of substances with alpha-blocking properties It is possible to reduce the above-mentioned toxicity by administering the drug to a patient.

The claimed product can be administered orally 30 minutes before the intravenous injection of norepinephrine. given.

b) Results The above results indicate that the 50% effective dose (ED,.), i.e., the biological expressed in the form of a dose per mg, kg-' of protection.

The ED5° values corresponding to the claimed products are shown in Table IV.

Compounds B1450, B1509, B1567, B1614, B1697, BI7 +1 and BI713 showed excellent protection against norepinephrine toxicity and sequestration. Demonstrated activity in the affected organs is confirmed.

IV Activity in rabbit urethral hypertonia a) Policy By intravenously injecting norepinephrine into anesthetized rabbits, arterial pressure and urine Road pressure increases. Such hypertonicity makes molecules with alpha-blocking properties It can be suppressed by administering it in advance.

This effect is due to the 50% inhibitory dose (IDI), i.e. the increase in arterial and urethral pressure. It is evaluated as the dose that suppresses the effect by 50%. IDs for both pressures. The value of the By comparing the characteristics of the urethra, we can discover the special characteristics of the urethra.

111 [N Activity in rabbit urethral pressure The above results indicate that the product is more effective on urethral pressure than on arterial pressure.

Therefore, the products of the invention have extremely valuable pharmacological properties and their toxicity is significant. It is possible to use it for treatment because it has a low temperature.

The products of the invention are therefore of particular interest in human or veterinary medicine, especially in urethral hypertonia. It can be used to treat related urinary disorders.

The above products can be administered by common routes (parenteral, oral, rectal) or by pharmaceutically acceptable methods. It can be administered by topical route with excipients, either solid or liquid. (e.g. in the form of injectable preparations, tablets, gelatin capsules or granules) It is possible to The dosage depends, among other things, on the type and severity of the disease being treated and the method of administration. It can be varied within a wide range depending on the situation.

The dosage for adults is -0°1 to 0.5° per day when administered parenterally. g, and when administered orally, in the range -0.25 to 4 g per day. What is the most common thing?

Such pharmaceutical compositions form the main part of the invention. The method of preparing them is This further forms the main part of the present invention.

The above method of preparation involves mixing an effective amount of a compound of formula I with suitable excipients. consists of doing.

Finally, the present invention relates to urinary disorders particularly related to benign prostatic hyperplasia or urethral hypertonia. Relates to the use of compounds of formula (1) in the preparation of medicaments useful for the treatment of.

,,, Continuation of PCT/FR93100633 front page (72) Inventor Tsuru, Patrick France 94550 Chevilly L'Alu Lu des Briunis 15 (72) Inventor: Danrayer, Bernard France 78300 Poois Rue ・De・

Claims (7)

[Claims] 1. General formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula: -R1, R2 and R2 are are the same or different and selected from a hydrogen atom, a hydroxyl group and a methoxy group; -R4 is selected from hydrogen atoms and alkyl groups having 1 to 5 carbon atoms; -n represents an integer from 1 to 3; When n corresponds to 1, R1, R2 and R2 are the 3rd and 4th positions of the phenyl ring At the same time, R1, R2 and R2 do not represent a hydroxyl group at the same time, and R1, R2 and R2 simultaneously represent a hydrogen atom. When representing a child, R4 does not represent a methyl radical; When n matches 3, at least one of R1, R2 and R2 represents a hydroxyl group; vinegar;〕 Compounds in the form of racemic acids or enantiomers represented by and their addition salts. 2. Formula (II): There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) [In the formula: -R1, R2, R3, R4 and and n are the same as defined in claim 1;] A compound represented by is mixed with a solvent such as sodium borohydride in a solvent such as methanol. Reduce using a reducing agent and, if appropriate, salt the resulting compound with an inorganic or organic acid. A method for preparing a compound of formula (I) according to claim 1, which comprises converting. 3. The compound of formula (II) above has a hydrogen acid acceptor such as triethylamine. Formula (III) in a suitable solvent such as tetrahydrofuran: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) [In the formula: -R1, R2 and R2 are Same as the definition in claim 1; -X represents a halogen atom;] The ketone represented by formula (IV): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) [In the formula: -R4 is Reacts with O-alkoxyphenylpiperazine represented by 3. The method according to claim 2, wherein the method is obtained by: 4. General formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula: -R1, R2 and R1 are are the same or different and selected from a hydrogen atom, a hydroxyl group and a methoxy group; -R4 is selected from hydrogen atoms and alkyl groups having 1 to 5 carbon atoms; -n represents an integer from 1 to 3; When n equals 1, R1, R2 and R2 are the 3rd and 4th positions of the phenyl ring Therapeutically active substances and Compounds and addition salts thereof. 5. a therapeutically effective amount of at least one general formula (I); ▲ mathematical formula, chemical formula, table; etc.▼(I) [In the formula: -R1, R2 and R2 are each the same or different. -R4 is selected from a hydrogen atom, a hydroxyl group and a methoxy group; an alkyl group having 5 carbon atoms; -n represents an integer from 1 to 3: When n equals 1, R1, R2 and R2 are at the 3- and 4-positions of the phenyl ring. do not simultaneously represent hydroxyl groups; or Containing one of the pharmaceutically acceptable salts in a pharmaceutically acceptable excipient, excipient or base drugs useful in the treatment of humans or animals. 6. A therapeutically effective amount of at least one general formula (I): ▲ mathematical formula, chemical formula, table etc.▼(I) [In the formula: -R1, R2 and R2 are each the same or different. -R4 is selected from a hydrogen atom, a hydroxyl group and a methoxy group; an alkyl group having 5 carbon atoms; -n represents an integer from 1 to 3; When n equals 1, R1, R2 and R3 are the 3rd and 4th positions of the phenyl ring do not simultaneously represent hydroxyl groups; or Containing one of the pharmaceutically acceptable salts in a pharmaceutically acceptable excipient, excipient or base treatment of the urinary system, especially those specifically related to urethral hypertonia or benign prostatic hyperplasia. Drugs useful in treating urinary disorders. 7. General formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula: -R1, R2 and R2 are are the same or different and selected from a hydrogen atom, a hydroxyl group and a methoxy group; -R4 is selected from hydrogen atoms and alkyl groups having 1 to 5 carbon atoms; -n represents an integer from 1 to 3;] Compounds represented by Methods used in the preparation of drugs useful in the treatment of diseases.